Niraparib Compositions

ABSTRACT

The present invention relates to compositions comprising the compound niraparib, in particular certain solid forms of niraparib.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/477,411, filed Mar. 27, 2017, which is incorporated herein byreference in its entirety.

Niraparib is an orally active and potent poly (ADP-ribose) polymerase,or PARP, inhibitor. Niraparib and pharmaceutically acceptable saltsthereof, are disclosed in International Publication No. WO2007/113596and European Patent No. EP2007733B1; International Publication No.WO2008/084261 and U.S. Pat. No. 8,071,623; and International PublicationNo. WO2009/087381 and U.S. Pat. No. 8,436,185. Methods of makingniraparib and pharmaceutically acceptable salts thereof are disclosed ininternational Publication Nos. WO2014/088983 and WO2014/088984. Methodsto treat cancer with niraparib and pharmaceutically acceptable saltsthereof are disclosed in U.S. Provisional Patent Application Nos.62/356,461, 62/402,427, 62/470,141, and PCT application PCT/US17/40039.The contents of each of the foregoing references are incorporated hereinby reference in their entirety.

PARP is a family of proteins involved in many functions in a cell,including DNA repair, gene expression, cell cycle control, intracellulartrafficking and energy metabolism. PARP proteins play key roles insingle strand break repair through the base excision repair pathway.PARP inhibitors have shown activity as a monotherapy against tumors withexisting DNA repair defects, such as BRCA1 and BRCA2, and as acombination therapy when administered together with anti-cancer agentsthat induce DNA damage.

Despite several advances in treatment of ovarian cancer, most patientseventually relapse, and subsequent responses to additional treatment areoften limited in duration. Women with germline BRCA1 or BRCA2 mutationshave an increased risk for developing high grade serous ovarian cancer(HGSOC), and their tumors appear to be particularly sensitive totreatment with a PARP inhibitor. In addition, published scientificliterature indicates that patients with platinum sensitive HGSOC who donot have germline BRCA1 or BRCA2 mutations may also experience clinicalbenefit from treatment with a PARP inhibitor.

It is estimated that 5% to 10% of women who are diagnosed with breastcancer, or more than 15,000 women each year, carry a germline mutationin either their BRCA1 or BRCA2 genes. The development of cancer in thesewomen involves the dysfunction of a key DNA repair pathway known ashomologous recombination. While cancer cells can maintain viabilitydespite disruption of the homologous recombination pathway, they becomeparticularly vulnerable to chemotherapy if an alternative DNA repairpathway is disrupted. This is known as synthetic lethality a situationwhere the individual loss of either repair pathway is compatible withcell viability; but the simultaneous loss of both pathways results incancer cell deaths. Since PARP inhibitors block DNA repair, in thecontext of cancer cells with the BRCA mutation, PARP inhibition resultsin synthetic lethality. For this reason, patients with germlinemutations in a BRCA gene show marked clinical benefit that followstreatment with a PARP inhibitor.

One embodiment provides a composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Anotherembodiment provides the composition wherein the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-raypowder diffraction pattern substantially as shown in FIG. 1. Anotherembodiment provides the composition where the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by at least one X-ray diffraction pattern reflectionselected from a 2θ value of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2,18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0.2. Anotherembodiment provides the composition wherein the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2.Another embodiment provides the composition wherein the crystalline FormI is characterized by X-ray diffraction pattern reflections at 2θ valuesof 9.5±0.2 and 26.0±0.2. Another embodiment provides the compositionwherein the crystalline Form I is characterized by X-ray diffractionpattern reflections at 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2,18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment providesthe composition wherein the crystalline Form I is characterized by atleast one X-ray diffraction pattern reflection selected from a 2θ valueof 12 4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±10.2, 25.6±0.2, and26.9±0.2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by at least two X-ray diffractionpattern reflections selected from a 2θ value of 12 4±0.2, 13 2±0.2,17.4±0.2, 18.4±0.2, 21.0±0 2, 25.6±0 2, and 26.9±0.2 Another embodimentprovides the composition wherein the crystalline Form 1 is characterizedby at least three X-ray diffraction pattern reflections selected from a2θ value of 12.4±0.2, 13 2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2,and 26.9±0.2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by at least four X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodimentprovides the composition wherein the crystalline Form I is characterizedby a scanning differential calorimetry pattern substantially as shown inFIG. 2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by a Raman spectroscopy patternsubstantially as shown in FIG. 3. Another embodiment provides thecomposition wherein the crystalline Form I is characterized by aninfrared spectroscopy pattern substantially as shown in FIG. 4. Anotherembodiment provides the composition wherein the crystalline Form I ischaracterized by a dynamic water vapor sorption pattern substantially asshown in FIG. 5. Another embodiment provides the composition wherein thepresence of Form III is characterized by at least one X-ray diffractionpattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or22.8±0.2.

Another embodiment provides the composition wherein substantially freeof Form II and Form III means less than about 20% (w/w) combined totalweight for Form II and Form I compared to the combined total weight ofForm I, Form II and Form III. Another embodiment provides thecomposition wherein substantially free of Form II and Form III meansless than about 15% (w/w) combined total weight for Form II and Form IIIcompared to the combined total weight of Form I, Form II and Form III.Another embodiment provides the composition wherein substantially freeof Form II and Form III means less than about 10% (w/w) combined totalweight for Form II and Form III compared to the combined total weight ofForm I, Form II and Form III. Another embodiment provides thecomposition wherein substantially free of Form II and Form III meansless than about 8% (w/w) combined total weight for Form II and Form IIcompared to the combined total weight of Form I, Form II and Form III.Another embodiment provides the composition wherein substantially freeof Form II and Form II means less than about 6% (w/w) combined totalweight for Form II and Form III compared to the combined total weight ofForm I, Form II and Form III. Another embodiment provides thecomposition wherein substantially free of Form II and Form III meansless than about 4% (w/w) combined total weight for Form II and Form IIIcompared to the combined total weight of Form I, Form II and Form III.Another embodiment provides the composition wherein substantially freeof Form II and Form III means less than about 3% (w/w) combined totalweight for Form II and Form III compared to the combined total weight ofForm I, Form II and Form III. Another embodiment provides thecomposition wherein substantially free of Form II and Form III meansless than about 2% (w/w) combined total weight for Form II and Form IIIcompared to the combined total weight of Form I, Form II and Form III.Another embodiment provides the composition wherein substantially freeof Form II and Form III means less than about 1% (w/w) combined totalweight for Form II and Form III compared to the combined total weight ofForm I, Form II and Form III.

One embodiment provides a composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form II2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. In oneembodiment, crystalline Form II is characterized by at least one X-raydiffraction pattern reflection selected from a 2θ value of 9.7±0.3,12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3. In one embodiment,crystalline Form II has an X-ray powder diffraction patternsubstantially as shown in FIG. 9 for Form II.

One embodiment provides a composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides crystalline Form III characterized by at least oneX-ray diffraction pattern reflection selected from a 2θ value of17.8±0.2, 19.0±0.2, or 22.8±0.2. One embodiment provides crystallineForm II that has an X-ray powder diffraction pattern substantially asshown in FIG. 9 for Form III. One embodiment provides crystalline FormIII of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide thathas an X-ray powder diffraction pattern substantially as shown in FIG.7. One embodiment provides crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a dynamic water vapor sorption pattern substantially asshown in FIG. 8. One embodiment provides crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a scanning differential calorimetry patternsubstantially as shown in FIG. 2.

One embodiment provides a method of making crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, comprisingdissolving a composition comprising Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form IIIof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or amixture thereof, in a solvent having a water:organic solvent ratio ofabout 10:1 to about 400:1 (v/v), and crystallizing the crystalline FormI. Another embodiment provides the method wherein the water:organicsolvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v),about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v). Anotherembodiment provides the composition wherein the organic solvent is apolar solvent, a polar protic solvent, a polar aprotic solvent, anether-containing solvent, or any combination thereof. Another embodimentprovides the composition wherein the organic solvent is 2-propanol,acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid,methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combinationthereof. Another embodiment provides the composition wherein the organicsolvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butylether, dioxane, dimethyl sulfoxide, or any combination thereof. Anotherembodiment provides the composition wherein the organic solvent is2-propanol, acetic acid, formic acid, or any combination thereof.Another embodiment provides the composition wherein the organic solventand water is heated prior to crystallization.

One embodiment provides a composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide prepared bydissolving a composition comprising Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form IIIof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or amixture thereof, in a solvent having a water:organic solvent ratio ofabout 10:1 to about 400:1 (v/v), and crystallizing the crystalline FormI. Another embodiment provides the composition wherein the water:organicsolvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v),about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v). Anotherembodiment provides the composition wherein the organic solvent is apolar solvent, a polar protic solvent, a polar aprotic solvent, anether-containing solvent, or any combination thereof. Another embodimentprovides the composition wherein the organic solvent is 2-propanol,acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid,methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combinationthereof. Another embodiment provides the composition wherein the organicsolvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butylether, dioxane, dimethyl sulfoxide, or any combination thereof. Anotherembodiment provides the composition wherein the organic solvent is2-propanol, acetic acid, formic acid, or any combination thereof.Another embodiment provides the composition wherein the organic solventand water is heated prior to crystallization.

In some embodiments, a composition described herein is a pharmaceuticalcomposition (e.g., a pharmaceutical composition comprising at least onepharmaceutically acceptable excipient). One embodiment provides apharmaceutical composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and atleast one pharmaceutically acceptable excipient. Another embodimentprovides the pharmaceutical composition wherein the composition is in anoral dosage form. Another embodiment provides the pharmaceuticalcomposition wherein the oral dosage form is a tablet or capsule. Oneembodiment provides an article of manufacture comprising multiple unitdoses of the pharmaceutical composition in a sealed container withwritten instructions for use. In another embodiment, the article ofmanufacture comprising multiple unit doses of the pharmaceuticalcomposition in a sealed container with written instructions for use,further comprises an induction seal, desiccant, or any combinationthereof.

One embodiment provides a method for treating cancer in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of the pharmaceutical composition comprisingcrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and at least onepharmaceutically acceptable excipient, wherein the cancer is selectedfrom the group consisting of ovarian cancer, breast cancer, cervicalcancer, endometrial cancer, prostate cancer, testicular cancer,pancreatic cancer, esophageal cancer, head and neck cancer, gastriccancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectalcancer, thyroid cancer, brain and central nervous system cancers,glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer,keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma,bladder cancer, liver cancer, kidney cancer, myeloma, lymphoma, andcombinations thereof.

One embodiment provides a method for treating cancer in a patient havingbeen diagnosed with cancer comprising administering to said patient atherapeutically effective amount of the pharmaceutical comprisingcrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and atleast one pharmaceutically acceptable excipient, wherein the cancer isselected from the group consisting of ovarian cancer, breast cancer,cervical cancer, endometrial cancer, prostate cancer, testicular cancer,pancreatic cancer, esophageal cancer, head and neck cancer, gastriccancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectalcancer, thyroid cancer, brain and central nervous system cancers,glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer,keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma,bladder cancer, liver cancer, kidney cancer, myeloma, lymphoma, andcombinations thereof. Another embodiment provides the method wherein thecancer is selected from the group consisting of ovarian cancer,fallopian tube cancer, primary peritoneal cancer, and combinationsthereof. Another embodiment provides the method wherein the cancer is arecurrent cancer. Another embodiment provides the method wherein thesubject is a human subject. Another embodiment provides the methodwherein the human subject was previously treated with a chemotherapy.Another embodiment provides the method wherein the chemotherapy is aplatinum-based chemotherapy. Another embodiment provides the methodwherein the human subject had a complete or partial response to thechemotherapy. Another embodiment provides the method wherein thepharmaceutical composition is administered once per day, twice per day,three times per day, or four times per day. Another embodiment providesthe method wherein the pharmaceutical composition is administered onceper week, twice per week, three times per week, or four times per week.Another embodiment provides the method wherein the pharmaceuticalcomposition is administered every other day. Another embodiment providesthe method wherein the pharmaceutical composition is administered onceper day. Another embodiment provides the method wherein the total doseof a the pharmaceutical composition administered within a 24 hour periodis about 1 mg to about 1000 mg. Another embodiment provides the methodwherein the total dose is about 1000 mg, about 900 mg, about 800 mg,about 700 mg, about 600 mg, about 500 mg, about 400 mg, about 300 mg,about 200 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 10 mg,about 5 mg, or about 1 mg. Another embodiment provides the methodwherein the pharmaceutical composition is administered once per day andthe total daily dose is about 300 mg. Another embodiment provides themethod wherein the administration is oral administration.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the invention are set forth with particularity in theappended claims. A better understanding of the features and advantagesof the present invention will be obtained by reference to the followingdetailed description that sets forth illustrative embodiments, in whichthe principles of the invention are utilized, and the accompanyingdrawings of which:

FIG. 1 shows an exemplary X-ray powder diffraction pattern forcrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 2 shows an exemplary scanning differential calorimetry pattern forcrystalline monohydrate Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 3 shows an exemplary Raman spectroscopy pattern for crystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 4 shows an exemplary infrared spectroscopy pattern for crystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 5 shows an exemplary dynamic water vapor sorption pattern forcrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 6 shows an overlay of exemplary X-ray powder diffraction patternsfor crystalline Form I, and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 7 shows an exemplary X-ray powder diffraction pattern forcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 8 shows an exemplary dynamic water vapor sorption pattern forcrystalline anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

FIG. 9 shows an overlay of exemplary X-ray powder diffraction patternsfor crystalline Form I, Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “cancer” includes both solid tumors and hematologicalmalignancies. Cancers include, but are not limited to, ovarian cancer,breast cancer, cervical cancer, endometrial cancer, prostate cancer,testicular cancer, pancreatic cancer, esophageal cancer, head and neckcancer, gastric cancer, bladder cancer, lung cancer (e.g.,adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), coloncancer, rectal cancer, thyroid cancer, brain and central nervous systemcancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoidcancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma,sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g.,hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma),myeloid disorders (e.g., AML, CML, myelodysplastic syndrome andpromyelocytic leukemia), and lymphoid disorders (e.g., leukemia,multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma,T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma).

The term “composition”, as in pharmaceutical composition, is intended toencompass a dug product comprising niraparib or its pharmaceuticallyacceptable salts, esters, solvates, polymorphs, stereoisomers ormixtures thereof, and the other inert ingredient(s) (pharmaceuticallyacceptable excipients). Such pharmaceutical compositions are synonymouswith “formulation” and “dosage form”. Pharmaceutical compositions of theinvention include, but are not limited to, granules, tablets (singlelayered tablets, multilayered tablets, mini tablets, bioadhesivetablets, caplets, matrix tablets, tablet within a tablet, mucoadhesivetablets, modified release tablets, orally disintegrating tablets,pulsatile release tablets, timed release tablets, delayed release,controlled release, extended release and sustained release tablets),capsules (hard and soft or liquid filled soft gelatin capsules), pills,troches, sachets, powders, microcapsules, minitablets, tablets incapsules and microspheres, matrix composition and the like. In someembodiments, the pharmaceutical composition refers to capsules. In someembodiments, the pharmaceutical composition refers to hard gelatincapsules or HPMC based capsules. In some embodiments, the pharmaceuticalcomposition refers to hard gelatin capsules.

“Diluents” increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pact (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar, monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like. Combinations of one or morediluents can also be used.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of the niraparib beingadministered that would be expected to relieve to some extent one ormore of the symptoms of the disease or condition being treated. Forexample, the result of administration of niraparib disclosed herein isreduction and/or alleviation of the signs, symptoms, or causes ofcancer. For example, an “effective amount” for therapeutic uses is theamount of niraparib, including a formulation as disclosed hereinrequired to provide a decrease or amelioration in disease symptomswithout undue adverse side effects. The term “therapeutically effectiveamount” includes, for example, a prophylactically effective amount. Itis understood that an “an effective amount” or a “therapeuticallyeffective amount” varies, in some embodiments, from subject to subject,due to variation in metabolism of the compound administered, age,weight, general condition of the subject, the condition being treated,the severity of the condition being treated, and the judgment of theprescribing physician.

The terms “enhance” or “enhancing” refers to an increase or prolongationof either the potency or duration of a desired effect of niraparib, or adiminution of any adverse symptomatology that is consequent upon theadministration of the therapeutic agent. Thus, in regard to enhancingthe effect of niraparib disclosed herein, the term “enhancing” refers tothe ability to increase or prolong, either in potency or duration, theeffect of other therapeutic agents that are used in combination withniraparib disclosed herein. An “enhancing-effective amount,” as usedherein, refers to an amount of niraparib or other therapeutic agentwhich is adequate to enhance the effect of another therapeutic agent orniraparib in a desired system. When used in a patient, amounts effectivefor this use will depend on the severity and course of the disease,disorder or condition, previous therapy, the patient's health status andresponse to the drugs, and the judgment of the treating physician.

The term “excipient” means a pharmacologically inactive component suchas a diluent, lubricant, surfactant, carrier, or the like. Excipientsthat are useful in preparing a pharmaceutical composition are generallysafe, non-toxic and are acceptable for human pharmaceutical use.Reference to an excipient includes both one and more than one suchexcipient. Co-processed excipients are also covered under the scope ofpresent invention.

“Filling agents” or “fillers” include compounds such as lactose, lactosemonohydrate, calcium carbonate, calcium phosphate, dibasic calciumphosphate, calcium sulfate, microcrystalline cellulose, cellulosepowder, dextrose, dextrates, dextran, starches, pregelatinized starch,sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,polyethylene glycol, and the like.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, magnesium stearate, calcium hydroxide, talc, sodiumstearyl fumarate, a hydrocarbon such as mineral oil, or hydrogenatedvegetable oil such as hydrogenated soybean oil (Sterotex®), higher fattyacids and their alkali-metal and alkaline earth metal salts, such asaluminum, calcium, magnesium, zinc, stearic acid, sodium stearates,glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodiumacetate, sodium chloride, leucine, a polyethylene glycol (e.g.,PEG-4000) or a methoxypolyethylene glycol such as Carbowax™, sodiumoleate, sodium benzoate, glyceryl behenate, polyethylene glycol,magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™,Cab-O-Sil®, a starch such as corn starch, silicone oil, a surfactant,and the like.

The term “subject” is used to mean an animal, preferably a mammal,including a human or non-human. The terms patient and subject may beused interchangeably.

A “therapeutically effective amount” or “effective amount” is thatamount of a pharmaceutical agent to achieve a pharmacological effect.The term “therapeutically effective amount” includes, for example, aprophylactically effective amount. An “effective amount” of niraparib isan amount needed to achieve a desired pharmacologic effect ortherapeutic improvement without undue adverse side effects. Theeffective amount of a niraparib will be selected by those skilled in theart depending on the particular patient and the disease. It isunderstood that “an effective amount” or a “therapeutically effectiveamount” can vary from subject to subject, due to variation in metabolismof niraparib, age, weight, general condition of the subject, thecondition being treated, the severity of the condition being treated,and the judgment of the prescribing physician. As used herein,amelioration or lessening of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any decrease of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that is attributed to orassociated with administration of the compound or composition.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition, for examplecancer, symptoms, preventing additional symptoms, ameliorating orpreventing the underlying metabolic causes of symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

As used herein, “weight percent,” “wt %,” “percent by weight,” “% byweight,” and variations thereof refer to the concentration of asubstance as the weight of that substance divided by the total weight ofthe composition and multiplied by 100.

Other objects, features, and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only.

Niraparib and Solid State Forms Thereof

The present invention relates to solid dosage forms of niraparib andpharmaceutically acceptable salts thereof (e.g., niraparib tosylatemonohydrate), including solid forms having desirable characteristicsfavorable for pharmaceutical development. Niraparib has the followingstructure:

Niraparib is an orally available, selective poly(ADP-ribose) polymerase(PARP) 1 and 2 inhibitor. Niraparib displays PARP 1 and 2 inhibitionwith TC₅₀=3.8 and 2.1 nM, respectively, and in a whole cell assay, itinhibited PARP activity with EC₅₀=4 nM and inhibited proliferation ofcancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10-100 nMrange (see Jones et al., Journal Medicinal Chemistry, 2009, 52,7170-7185). Methods of administering niraparib to cancer patients arealso described in WO2018/005818, which is hereby incorporated byreference in its entirety.

The chemical name for niraparib tosylate monohydrate is2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide4-methylbenzenesulfonate hydrate (1:1.1) and it has the followingchemical structure:

The empirical molecular formula for niraparib is C₂₆H₃₀N₄O₅S and itsmolecular weight is 510.61 g/mol. Niraparib tosylate monohydrate drugsubstance is a white to off-white, non-hygroscopic crystalline solid.Niraparib solubility is pH independent below the pKa of 9.95, with anaqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across thephysiological pH range.

Methods for preparation of niraparib include those described in WO2014/088983; WO 2014/088984; U.S. Pat. Nos. 8,071,623; 8,436,185, U.S.62/489,415 filed Apr. 24, 2017; and Jones et al., J. Med Chem.,52:7170-7185, 2009, each of which is incorporated by reference in itsentirety. Niraparib prepared according to these methods can be used inthe methods of preparation of the crystalline solid forms describedherein. For example, crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can beprepared from solvent systems comprising water (e.g., as described inExample 1 and Example 2). Crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can beproduced under anhydrous conditions. Crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can beproduced from crystalline Form I under heating conditions (e.g., asdescribed in Example 3).

Provided herein are crystalline solid forms of 4-toluenesufonate saltsof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Forexample, provided herein are crystalline solid forms of4-toluenesufonate salts of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide having 1:1stoichiometry.

Provided herein is crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. CrystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide isthe 4-toluenesulfonate salt and is a monohydrate. Crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is alsoreferred to by interchangeable terms such as: Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystallinemonohydrate Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystallineForm I of niraparib tosylate monohydrate; crystalline Form I; or Form I.Exemplary X-ray powder diffraction data for Form I is provided in FIG. 1and FIG. 6. FIG. 2 shows an exemplary scanning differential calorimetrypattern for crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. FIG. 3shows an exemplary Raman spectroscopy pattern for crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. FIG. 4shows an exemplary infrared spectroscopy pattern for crystalline Form Iof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. FIG. 5shows an exemplary dynamic water vapor sorption pattern for crystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

Provided herein is crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. CrystallineForm II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamideis the 4-toluenesulfonate salt and is a non-stoichiometric hydrate.Crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is alsoreferred to by interchangeable terms such as: Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystallineForm II of niraparib; crystalline Form I; or Form II.

Provided herein is crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. CrystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide isthe 4-toluenesulfonate salt and is an anhydrous form. Exemplary X-raypowder diffraction data for Form III is provided in FIG. 6 and FIG. 7.FIG. 2 shows an exemplary scanning differential calorimetry pattern forcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. FIG. 8shows an exemplary dynamic water vapor sorption pattern for crystallineanhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. CrystallineForm fil of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamideis also referred to by interchangeable terms such as: Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystallineanhydrous Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystallineForm III of niraparib; crystalline Form III; or Form III. FIG. 2 showsan exemplary scanning differential calorimetry pattern for crystallineForm II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

Solid forms of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide describedherein can have beneficial properties, including favorable propertiesfor use in methods of treatment or in methods of manufacture ofpharmaceutical formulations. For example, a hydrochloride salt of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has beenshown to be highly hygroscopic. By contrast, crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is anon-hygroscopic solid form having suitable solubility properties, aswell as favorable physical and chemical stability.

One embodiment provides a composition comprising crystalline Form I ofniraparib tosylate monohydrate substantially free of Form II and FormIII. Another embodiment provides the composition wherein the crystallineForm I of niraparib tosylate monohydrate has an X-ray powder diffractionpattern substantially as shown in FIG. 1. Another embodiment providesthe composition where the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by at least one X-ray diffraction pattern reflectionselected from a 2θ value of 9 5±0.2, 12.4±0.2, 13 2±0.2, 174±0.2,18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26 9±0.2 Anotherembodiment provides the composition wherein the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2.Another embodiment provides the composition wherein the crystalline FormI is characterized by X-ray diffraction pattern reflections at 2θ valuesof 9.5±0.2 and 26.0±0.2. Another embodiment provides the compositionwherein the crystalline Form I is characterized by X-ray diffractionpattern reflections at a 2θ values of 12.4±0.2, 13.2±0 2, 17.4±0.2,18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment providesthe composition wherein the crystalline Form I is characterized by atleast one X-ray diffraction pattern reflection selected from a 2θ valueof 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and26.9±0.2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by at least two X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodimentprovides the composition wherein the crystalline Form I is characterizedby at least three X-ray diffraction pattern reflections selected from a2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2,and 26.9±0.2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by at least four X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodimentprovides the composition wherein the crystalline Form I is characterizedby a scanning differential calorimetry pattern substantially as shown inFIG. 2. Another embodiment provides the composition wherein thecrystalline Form I is characterized by a Raman spectroscopy patternsubstantially as shown in FIG. 3. Another embodiment provides thecomposition wherein the crystalline Form I is characterized by aninfrared spectroscopy pattern substantially as shown in FIG. 4. Anotherembodiment provides the composition wherein the crystalline Form I ischaracterized by a dynamic water vapor sorption pattern substantially asshown in FIG. 5.

One embodiment provides a composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form II2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. In oneembodiment, crystalline Form III is characterized by at least one X-raydiffraction pattern reflection selected from a 2θ value of 9.7±0.3,12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3. In one embodiment,crystalline Form II has an X-ray powder diffraction patternsubstantially as shown in FIG. 9 for Form II.

One embodiment provides a composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides a composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Oneembodiment provides crystalline Form III characterized by at least oneX-ray diffraction pattern reflection selected from a 2θ value of17.8±0.2, 19.0±0.2, or 22.8±0.2. One embodiment provides crystallineForm III that has an X-ray powder diffraction pattern substantially asshown in FIG. 9 for Form III. One embodiment provides crystalline FormIII of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide thathas an X-ray powder diffraction pattern substantially as shown in FIG.7. One embodiment provides crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a dynamic water vapor sorption pattern substantially asshown in FIG. 8. One embodiment provides crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a scanning differential calorimetry patternsubstantially as shown in FIG. 2.

Niraparib is a selective poly(ADP-ribose) polymerase (PARP) I and 2inhibitor which selectively kills tumor cells in vitro and in mousexenograft models PARP inhibition leads to irreparable double strandbreaks (DSBs), use of the error-prone DNA repair pathway, resultantgenomic instability, and ultimately cell death. Additionally, PARPtrapped at genetic lesions as a result of the suppression ofautoparlyation can contribute to cytotoxicity.

ZEJULA™ is indicated for the maintenance or treatment of adult patientswith recurrent epithelial ovarian, fallopian tube, or primary peritonealcancer following a complete or partial response to platinum-basedchemotherapy. Each ZEJULA™ capsule contains 100 mg of niraparib (astosylate monohydrate). The hard capsules have a white body with “100 mg”printed in black ink, and a purple cap with “Niraparib” printed in whiteink. The recommended dose of ZEJULA™ as monotherapy is three 100 mgcapsules taken orally once daily, equivalent to a total daily dose of300 mg.

Provided herein is an oral composition containing niraparib or itspharmaceutically acceptable salts. In some embodiments, the oralcomposition includes from about 20 wt % to about 60 wt % of niraparibfor treatment of a disorder or condition such as cancer; and apharmaceutically acceptable carrier, wherein the niraparib isdistributed with substantial uniformity throughout the pharmaceuticallyacceptable carrier.

In some embodiments, the disorder or condition is cancer, for example,ovarian cancer.

In some embodiments, the niraparib is a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutically acceptable salt isniraparib tosylate monohydrate.

In some embodiments, the niraparib tosylate monohydrate is a crystallineForm I substantially free of Form II and Form III. Another embodimentprovides the composition wherein the crystalline Form I of niraparibtosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

In some embodiments, the pharmaceutical composition comprises about 50mg to about 300 mg of niraparib tosylate monohydrate. In someembodiments, the pharmaceutical composition comprises about 50 mg toabout 300 mg of niraparib tosylate monohydrate as a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe composition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1.

For example, the pharmaceutical composition can comprise about 100 mg toabout 200 mg of niraparib tosylate monohydrate. For example, thepharmaceutical composition can comprise about 125 mg to about 175 mg ofniraparib tosylate monohydrate.

The formulation can comprise one or more components, includingniraparib. The components can be combined to create a powder blend thatis used to fill capsules. For example, the powder blend can be filledinto gelatin capsules, such as size 0 gelatin capsules.

The niraparib may be present in the formulation as a pharmaceuticallyacceptable salt. For example, the niraparib can be niraparib tosylatemonohydrate.

The formulation can comprise one or more diluents. For example, theformulation can comprise lactose monohydrate.

The formulation can comprise one or more lubricants. For example, Forexample, the formulation can comprise magnesium stearate.

An exemplary niraparib formulation of the present invention comprises100 mg of niraparib (based on free base, 1.000 mg niraparib anhydrousfree base is equivalent to 1.594 mg niraparib tosylate monohydrate),254.5 mg of lactose monohydrate and magnesium stearate. An exemplaryniraparib formulation of the present invention comprises 100 mg ofniraparib (based on free base, 1.000 mg niraparib anhydrous free base isequivalent to 1.594 mg niraparib tosylate monohydrate), 254.5 mg oflactose monohydrate, and magnesium stearate. It may also optionallycomprise tartrazine.

Niraparib Concentration/Amount

By means of methods and compositions described herein, formulations canbe made that achieve therapeutically effective pharmacokinetic profiles.For example, therapeutically effective doses of niraparib can beadministered once, twice or three times daily in capsules using themanufacturing methods and compositions that have been described hereinto achieve these results. In some embodiments, the niraparib is presentin an amount of from about 20-80 wt %, about 45-70 wt %, about 40-50 wt%, about 45-55 wt %, about 50-60 wt %, about 55-65 wt %, about 60-70 wt%, about 65-75 wt %, about 70-80 wt %, or about 40-60 wt %. In someembodiments, the niraparib is niraparib tosylate monohydrate is acrystalline Form I substantially free of Form II and Form III. Anotherembodiment provides the composition wherein the crystalline Form I ofniraparib tosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

In some embodiments, the compositions described herein have aconcentration of niraparib of from about 1% to about 50%, from about 5%to about 50%, from about 10% to about 50%, from about 15% to about 50%,from about 20%, to about 50%, from about 25% to about 50%, from about30% to about 50%, from about 35% to about 50%, from about 40% to about50%, or from about 45% to about 50%, by weight of the composition. Insome embodiments, the niraparib is niraparib tosylate monohydrate is acrystalline Form I substantially free of Form II and Form III. Anotherembodiment provides the composition wherein the crystalline Form I ofniraparib tosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

In some embodiments, the compositions described herein have aconcentration of niraparib of from about 1% to about 45%, from about 5%to about 45%, from about 10% to about 45%, from about 15% to about 45%,from about 20% to about 45%, from about 25% to about 45%, from about 30%to about 45%, from about 35% to about 45%, or from about 40% to about45% by weight of the composition. In some embodiments, the niraparib isniraparib tosylate monohydrate is a crystalline Form I substantiallyfree of Form II and Form III. Another embodiment provides thecomposition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1.

In some embodiments, the compositions described herein have aconcentration of niraparib of from about 1% to about 40%, from about 5%to about 40%, from about 10% to about 40%, from about 15% to about 40%,from about 20% to about 40%, from about 25% to about 40%, from about 30%to about 40%, from about 35% to about 40% by weight of the composition.In some embodiments, the niraparib is niraparib tosylate monohydrate isa crystalline Form I substantially free of Form I and Form III. Anotherembodiment provides the composition wherein the crystalline Form I ofniraparib tosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

In some embodiments, the compositions described herein have aconcentration of niraparib of from about 1% to about 35%, from about 5%to about 35%, from about 10% to about 35%, from about 15% to about 35%,from about 20% to about 35%, from about 25% to about 35%, or from about30% to about 35% by weight of the composition. In some embodiments, theniraparib is niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe composition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1.

In some embodiments, the compositions described herein have aconcentration of niraparib of about 1%, 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, or 50% by weight of the composition. In some embodiments,the compositions described herein have a concentration of niraparibtosylate monohydrate of about 19.16% by weight of the composition. Insome embodiments, the compositions described herein have a concentrationof niraparib tosylate monohydrate of about 38.32% by weight of thecomposition. In some embodiments, the compositions described herein havea concentration of niraparib tosylate monohydrate of about 57.48% byweight of the composition. In some embodiments, the compositionsdescribed herein have a concentration of niraparib tosylate monohydrateof about 76.64% by weight of the composition. In some embodiments, theniraparib is niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe composition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1.

In some embodiments, the compositions described herein have an amount ofniraparib of from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, theniraparib is niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe composition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1. For example, the compositions described herein can havean amount of niraparib tosylate monohydrate of from about 1 mg to about1000 mg, for example, from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 ng to 95 mg,90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg,170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg.

In some embodiments, the compositions described herein have an amount ofniraparib of about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg,100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or1000 mg. In some embodiments, the niraparib is niraparib tosylatemonohydrate is a crystalline Form I substantially free of Form II andForm III. Another embodiment provides the composition wherein thecrystalline Form I of niraparib tosylate monohydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 1. For example, thecompositions described herein can have an amount of niraparib tosylatemonohydrate of about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg,300 mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg,or 1000 mg.

In some embodiments, the compositions described herein have an amount ofniraparib of about 25 mg, about 50 mg, about 100 mg, about 150 mg, about200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about450 mg, or about 500 mg. For example, the compositions described hereincan have an amount of niraparib tosylate monohydrate of about 25 mg,about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.In some embodiments, the compositions described herein have an amount ofniraparib tosylate monohydrate of about 79.7 mg. In some embodiments,the compositions described herein have an amount of niraparib tosylatemonohydrate of about 159.4 mg. In some embodiments, the compositionsdescribed herein have an amount of niraparib tosylate monohydrate ofabout 159.4 mg, wherein the niraparib is niraparib tosylate monohydrateis a crystalline Form I substantially free of Form II and Form III. Insome embodiments, the compositions described herein have an amount ofniraparib tosylate monohydrate of about 159.4 mg, wherein the niraparibis niraparib tosylate monohydrate is a crystalline Form I substantiallyfree of Form II and Form III In some embodiments, the compositionsdescribed herein have an amount of niraparib tosylate monohydrate ofabout 159.4 mg, wherein the niraparib tosylate monohydrate is thecrystalline Form I with an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments, the compositionsdescribed herein have an amount of niraparib tosylate monohydrate ofabout 318.8 mg. In some embodiments, the compositions described hereinhave an amount of niraparib tosylate monohydrate of about 478.2 mg. Insome embodiments, the niraparib is niraparib tosylate monohydrate is acrystalline Form I substantially free of Form II and Form III. Anotherembodiment provides the composition wherein the crystalline Form I ofniraparib tosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

Pharmaceutically Acceptable Excipients

In some aspects, the pharmaceutical composition disclosed hereincomprises one or more pharmaceutically acceptable excipients. Exemplarypharmaceutically acceptable excipients for the purposes ofpharmaceutical compositions disclosed herein include, but are notlimited to, binders, disintegrants, superdisintegrants, lubricants,diluents, fillers, flavors, glidants, sorbents, solubilizers, chelatingagents, emulsifiers, thickening agents, dispersants, stabilizers,suspending agents, adsorbents, granulating agents, preservatives,buffers, coloring agents and sweeteners or combinations thereof.Examples of binders include microcrystalline cellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone,polyvinylpolypyrrolidone, carboxymethylcellulose calcium,carboxymethylcellulose sodium, ceratonia, chitosan, cottonseed oil,dextrates, dextrin, ethylcellulose, gelatin, glucose, glyceryl behenate,galactomannan polysaccharide, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, hypromellose, inulin, lactose,magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer,polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide,polymethacrylates, sodium alginate, sorbitol, starch, sucrose, sunfloweroil, vegetable oil, tocofersolan, zein, or combinations thereof.Examples of disintegrants include hydroxypropyl methylcellulose (HPMC),low substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium,sodium starch glycolate, lactose, magnesium aluminum silicate,methylcellulose, polacrilin potassium, sodium alginate, starch, orcombinations thereof. Examples of a lubricant include stearic acid,sodium stearyl fumarate, glyceryl behenate, calcium stearate, glycerinmonostearate, glyceryl palmitostearate, magnesium lauryl sulfate,mineral oil, palmitic acid, myristic acid, poloxamer, polyethyleneglycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, talc,zinc stearate, potassium benzoate, magnesium stearate or combinationsthereof. Examples of diluents include talc, ammonium alginate, calciumcarbonate, calcium lactate, calcium phosphate, calcium silicate, calciumsulfate, cellulose, cellulose acetate, corn starch, dextrates, dextrin,dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glycerylpalmitostearate, isomalt, kaolin, lactitol, lactose, magnesiumcarbonate, magnesium oxide, maltodextrin, maltose, mannitol,microcrystalline cellulose, polydextrose, polymethacrylates,simethicone, sodium alginate, sodium chloride, sorbitol, starch,sucrose, sulfobutylether β-cyclodextrin, tragacanth, trehalose, xylitol,or combinations thereof. In some embodiments, the pharmaceuticallyacceptable excipient is hydroxypropyl methylcellulose (HPMC). In someembodiments, the pharmaceutically acceptable excipient is lowsubstituted hydroxypropyl cellulose (L-HPC). In some embodiments, thepharmaceutically acceptable excipient is lactose. In some embodiments,the pharmaceutically acceptable excipient is lactose monohydrate. Insome embodiments, the pharmaceutically acceptable excipient is magnesiumstearate. In some embodiments, the pharmaceutically acceptable excipientis lactose monohydrate and magnesium stearate.

Various useful fillers or diluents include, but are not limited tocalcium carbonate (Barcroft™, MagGran™, MLillicarb™, Pharma-Carb™,Precarb™, Sturcal™, Vivapres Ca™), calcium phosphate, dibasic anhydrous(Emcompress Anhydrous™, Fujicalin™), calcium phosphate, dibasicdihydrate (Calstar™, Di-Cafos™, Emcompress™), calcium phosphate tribasic(Tri-Cafos™, TRI-TAB™), calcium sulphate (Destab™, Drierite™, SnowWhite™, Cal-Tab™, Compactrol™), cellulose powdered (Arbocel™, Elcema™,Sanacet™), silicified microcrystailine cellulose, cellulose acetate,compressible sugar (Di-Pac™), confectioner's sugar, dextrates (Candex™,Emdex™), dextrin (Avedex™, Caloreen™, Primogran W™), dextrose (Caridex™,Dextrofin™, Tab fine D-100™), fructose (Fructofin™, Krystar™), kaolin(Lion™, Sim 90™), lactitol (Finlac DC™, Finlac MCX™), lactose(Anhydrox™, CapsuLac™, Fast-FloT™, FlowLac™, GranuLac™, inhaLac™,Lactochem™, Lactohaie™, Lactopress™, Microfme™, Microtose™, Pharmatose™,Prisma Lac™, Respitose™, SacheLac™, SorboLac™, Super-Tab™, Tablettose™,Wyndale™, Zeparox™), lactose monohydrate, magnesium carbonate, magnesiumoxide (MagGran MO™), maltodextrin (C*Dry MD™, Lycatab DSH™, Maldex™,Maitagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star-Dri™),maltose (Advantose 100™), mannitol (Mannogem™, Pearlitol™),microcrystalline cellulose (Avicel PH™, Celex™, Celpherem, Ceolus KG™,Emcocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™),simethicone (Dow Corning Q7-2243 LVA™, Cow Coming Q7-2587™, SentrySimethicone™), sodium alginate (Keltone™, Protanal™), sodium chloride(Alberger™), sorbitol (Liponec 70-NC™, Liponic 76-NCv, Meritol™,Neosorb™, Sorbitol Instant™, Sorbogem™), starch (Flufiex W™, InstantPure-Cote™, Melojej™, Meritena Paygel 55™, Perfectamyl D6PH™,Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™,Tablet White™), pregelatinized starch, sucrose, trehalose and xylitol,or mixtures thereof.

In some embodiments, a filler such as lactose monohydrate is present inan amount of about 5-90% by weight. In some embodiments, a filler suchas lactose monohydrate is present in an amount of about 5-80% by weight.In some embodiments, a filler such as lactose monohydrate is present inan amount of about 5-70% by weight. In some embodiments, a filler suchas lactose monohydrate is present in an amount of about 5-60% by weight.In some embodiments, a filler such as lactose monohydrate is present inan amount of about 5-50% by weight. In some embodiments, a filler suchas lactose monohydrate is present in an amount of about 5-40% by weight.In some embodiments, a filler such as lactose monohydrate is present inan amount of about 5-30% by weight. In some embodiments, a filler suchas lactose monohydrate is present in an amount of about 25-90% byweight. In some embodiments, a filler such as lactose monohydrate ispresent in an amount of about 25-80% by weight. In some embodiments, afiller such as lactose monohydrate is present in an amount of about25-70% by weight. In some embodiments, a filler such as lactosemonohydrate is present in an amount of about 25-60% by weight. In someembodiments, a filler such as lactose monohydrate is present in anamount of about 25-50% by weight. In some embodiments, a filler such aslactose monohydrate is present in an amount of about 25-40% by weight.In some embodiments, a filler such as lactose monohydrate is present inan amount of about 40-90% by weight. In some embodiments, a filler suchas lactose monohydrate is present in an amount of about 40-800% byweight. In some embodiments, a tiller such as lactose monohydrate ispresent in an amount of about 40-70% by weight. In some embodiments, afiller such as lactose monohydrate is present in an amount of about40-60% by weight. In some embodiments, a filler such as lactosemonohydrate is present in an amount of about 40-50% by weight. In someembodiments, a filler such as lactose monohydrate is present in anamount of about 40% by weight. In some embodiments, a filler such aslactose monohydrate is present in an amount of about 50% by weight. Insome embodiments, a filler such as lactose monohydrate is present in anamount of about 60% by weight. In some embodiments, a filler such aslactose monohydrate is present in an amount of about 70% by weight. Insome embodiments, a filler such as lactose monohydrate is present in anamount of about 80% by weight.

In some embodiments, a filler such as lactose monohydrate is present inan amount of from about 25 mg to about 1000 mg, from about 50 mg toabout 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg toabout 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg toabout 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg toabout 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg toabout 1000 mg, or from about 500 mg to about 1000 mg. For example, afiller such as lactose monohydrate can be present in an amount of fromabout 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, fromabout 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, fromabout 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, fromabout 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, fromabout 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, orfrom about 500 mg to about 1000 mg.

In some embodiments, a filler such as lactose monohydrate is present inan amount of from about 25 mg to about 50 mg, from about 50 mg to about100 mg, from about 100 mg to about 150 mg, from about 150 mg to about200 mg, from about 200 mg to about 250 mg, from about 250 mg to about300 mg, from about 300 mg to about 350 mg, from about 350 mg to about400 mg, from about 400 mg to about 450 mg, from about 450 mg to about500 mg, or from about 500 mg to about 550 mg. For example, a filler suchas lactose monohydrate can be present in an amount of from about 25 mgto about 50 mg, from about 50 mg to about 100 mg, from about 100 mg toabout 150 mg, from about 150 mg to about 200 mg, from about 200 mg toabout 250 mg, from about 250 mg to about 300 mg, from about 300 mg toabout 350 mg, from about 350 mg to about 400 mg, from about 400 mg toabout 450 mg, from about 450 mg to about 500 mg, or from about 500 mg toabout 550 mg.

In some embodiments, a filler such as lactose monohydrate is present inan amount of about 15 mg, about 25 mg, about 50 mg, about 100 mg, about150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about400 mg, about 450 mg, or about 500 mg. For example, a filler such aslactose monohydrate can be present in an amount of about 15 mg, about 25mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.In some embodiments, a filler such as lactose monohydrate is present inan amount of about 334.2 mg. In some embodiments, a filler such aslactose monohydrate is present in an amount of about 254.5 mg. In someembodiments, a filler such as lactose monohydrate is present in anamount of about 174.8 mg. In some embodiments, a filler such as lactosemonohydrate is present in an amount of about 95.1 mg. In someembodiments, a filler such as lactose monohydrate is present in anamount of about 15.4 mg.

Various useful disintegrants include, but are not limited to, alginicacid (Protacid™, Satialgine HS™), calcium phosphate, tribasic(TRI-TAB™), carboxymethylcellulose calcium (ECG 505™),carboxymethylcellulose sodium (Akucell™, Finnfix™, Nymcel Tylose CB™),colloidal silicon dioxide (Aerosil™, Cab-O-Sil™, Wacker HDK™),croscarmellose sodium (Ac-Di-Sol™, Pharmacel XL™, Primellose™, Solutab™,Vivasol™), crospovidone (Collison CL™, Collison CL-M™, PolyplasdoneXL™), docusate sodium, guar gum (Meyprodor™, Meyprofm™, Meyproguar™),low substituted hydroxypropyl cellulose, magnesium aluminum silicate(Magnabite™, Neusilin™, Pharmsorb™, Veegum™), methylcellulose(Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, CeoiusKG™, Emcoel™, Ethispheres™, Fibrocel™, Pharmacel™, Vivapur™), povidone(Collison™, Plasdone™) sodium alginate (Kelcosol™, Ketone™, Protanal™),sodium starch glycolate, polacrilin potassium (Amberlite IRP887™),silicified microcrystalline cellulose (ProSotv™), starch (Aytex P™,Fluftex W™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™,Pure-Bind™, Pure-Cote™, Pure-Dent™, Purity 21™, Purity 826™, TabletWhite™) or pre-gelatinized starch (Lycatab PGS™, Merigel™, National78-155™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch1500 G™, Tablitz™, Unipure LD™), or mixtures thereof. In someembodiments, a disintegrant is optionally used in an amount of about0-10% by weight. In some embodiments, a disintegrant is present in anamount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 65 mg to 70 mg, 70mg to 75 mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95mg, or 95 mg to 100 mg. In some embodiments, a disintegrant is presentin an amount of about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9mg, 11 mg, 13 mg, 15 mg, 17 mg, 19 mg, 21 mg, 23 mg, 25 mg, 27.5 mg, 30mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

Various useful lubricants include, but are not limited to, calciumstearate (HyQual™), glycerine monostearate (Imwitor™ 191 and 900, KesscoGMS5™, 450 and 600, Myvaplex 600P™, Myvatex™, Rita GMS™, Stepan GMS™,Tegin™, Tegin™ 503 and 515, Tegin 4100™, Tegin M™, Unimate GMS™),glyceryl behenate (Compritol 888 ATO™), glyceryl palmitostearate(Precirol ATO 5™), hydrogenated castor oil (Castorwax MP 80™, Croduret™,Cutina HR™, Fancol™, Simulsol 1293™), hydrogenated vegetable oil 0 typeI (Sterotex™, Dynasan P60™, Hydrocote™, Lipovol HS-K™, Sterotex HM™),magnesium lauryl sulphate, magnesium stearate, medium-chaintriglycerides (Captex 300™, Labrafac CC™, Miglyol 810™, Neobee M5™,Nesatol™, Waglinol 3/9280™), poloxamer (Pluronic™, Synperonic™),polyethylene 5 glycol (Carbowax Sentry™, Lipo™, Lipoxol™, Lutrol E™,Pluriol E™), sodium benzoate (Antimol™), sodium chloride, sodium laurylsulphate (Elfan 240™, Texapon KI 2P™), sodium stearyl fumarate (Pruv™),stearic acid (Hystrene™, Industrene™, Kortacid 1895™, Pristerene™), talc(Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, 0 Magsil Star™,Superiore™), sucrose stearate (Surfhope SE Pharma D-1803 F™) and zincstearate (HyQual™) or mixtures thereof. Examples of suitable lubricantsinclude, but are not limited to, magnesium stearate, calcium stearate,zinc stearate, stearic acid, talc, glyceryl behenate, polyethyleneglycol, polyethylene oxide polymers, sodium lauryl sulfate, magnesiumlauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine,colloidal silica, and others as known in the art. In some embodiments alubricant is magnesium stearate.

In some embodiments, a lubricant such as magnesium stearate is presentin an amount of about 0.1-5% by weight. In some embodiments, a lubricantsuch as magnesium stearate is present in an amount of about 0.1-2% byweight. In some embodiments, a lubricant such as magnesium stearate ispresent in an amount of about 0.1-1% by weight. In some embodiments, alubricant such as magnesium stearate is present in an amount of about0.1-0.75% by weight. In some embodiments, a lubricant such as magnesiumstearate is present in an amount of about 0.1-5% by weight. In someembodiments, a lubricant such as magnesium stearate is present in anamount of about 0.2-5% by weight. In some embodiments, a lubricant suchas magnesium stearate is present in an amount of about 0.2-2% by weight.In some embodiments, a lubricant such as magnesium stearate is presentin an amount of about 0.2-1% by weight. In some embodiments, a lubricantsuch as magnesium stearate is present in an amount of about 0.2-0.75% byweight. In some embodiments, a lubricant such as magnesium stearate ispresent in an amount of about 0.3% by weight. In some embodiments, alubricant such as magnesium stearate is present in an amount of about0.4% by weight. In some embodiments, a lubricant such as magnesiumstearate is present in an amount of about 0.5% by weight. In someembodiments, a lubricant such as magnesium stearate is present in anamount of about 0.6% by weight. In some embodiments, a lubricant such asmagnesium stearate is present in an amount of about 0.7% by weight. Insome embodiments, a lubricant is present in an amount of from about 0.01mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.25 mg,0.25 mg to 0.5 mg, 0.5 mg to 0.75 mg, 0.7 mg to 0.95 mg, 0.9 mg to 1.15mg, 1.1 mg to 1.35 mg, 1.3 mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 to 1.95mg, 1.9 mg to 2.15 mg, 2.1 mg to 2.35 mg, 2.3 mg to 2.55 mg, 2.5 mg to2.75 mg, 2.7 mg to 3.0 mg, 2.9 mg to 3.15 mg, 3.1 mg to 3.35 mg, 3.3 mgto 3.5 mg, 3.5 mg to 3.75 mg, 3.7 mg to 4.0 mg, 4.0 mg to 4.5 mg, 4.5 mgto 5.0 mg, 5.0 mg to 5.5 mg, 5.5 mg to 6.0 mg, 6.0 mg to 6.5 mg, 6.5 mgto 7.0 mg, 7.0 mg to 7.5 mg, 7.5 mg to 8.0 mg, 80 mg to 8.5 mg, 8.5 mgto 9.0 mg, 9.0 mg to 9.5 mg, or 9.5 mg to 10.0 mg. In some embodiments,a lubricant is present in an amount of about 0.01 mg, 0.05 mg, 0.1 mg,0.2 mg, 0.25 mg, 0.5 mg, 0.7 mg, 0.9 mg, 11 mg, 1.3 mg, 1.5 mg, 1.7 mg,1.9 mg, 2. mg, 2.3 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.1 mg, 3.3 mg, 3.5 mg,3.7 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg,8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, or 10.0 mg.

Various useful glidants include, but are not limited to, tribasiccalcium phosphate (TRI-TAB™), calcium silicate, cellulose, powdered(Sanacel™, Solka-Floe™), colloidal silicon dioxide (Aerosil™, Cab-O-SilM-5P™, Wacker HDK™), magnesium silicate, magnesium trisilicate, starch(Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™,Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™,Tablet White™) and talc (Luzenac Pharma™, Magsil Osmanthus™, MagsilStar™, Superiore™), or mixtures thereof. In some embodiments, a glidantis optionally used in an amount of about 0-15% by weight. In someembodiments, a glidant is present in an amount of from about 0.1 mg to0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mgto 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg,60 mg to 65 mg, 65 mg to 70 mg, 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg. In someembodiments, a glidant is present in an amount of about 0.1 mg, 0.5 mg,1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9 mg, 11 mg, 13 mg, 15 mg, 17 mg, 19 mg,21 mg, 23 mg, 25 mg, 27.5 mg, 30 mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg.

Pharmaceutically acceptable surfactants include, but are limited to bothnon-ionic and ionic surfactants suitable for use in pharmaceuticaldosage forms. Ionic surfactants may include one or more of anionic,cationic or zwitterionic surfactants. Various useful surfactantsinclude, but are not limited to, sodium lauryl sulfate, monooleate,monolaurate, monopalmitate, monostearate or another ester ofolyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin,stearyic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenericin oil, polyoxyethylene fatty acid glycerides, poloxamer, or anyother commercially available co-processed surfactant like SEPITRAP® 80or SEPITRAP® 4000 and mixtures thereof. In some embodiments, surfactantis optionally used in an amount of about 0-5% by weight. In someembodiments, a surfactant is present in an amount of from about 0.1 mgto 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg,5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, I 1 mg to 13.5 mg, 13mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mgto 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg,60 mg to 65 mg, 65 mg to 70 mg, 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg. In someembodiments, a surfactant is present in an amount of about 0.1 mg, 0.5mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9 mg, 11 mg, 13 mg, 15 mg, 17 mg, 19mg, 21 mg, 23 mg, 25 mg, 27.5 mg, 30 mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, or 100 mg.

Stability

In some embodiments, the pharmaceutical composition disclosed herein isstable for at least about: 30 days, 60 days, 90 days, 6 months, 1 year,18 months, 2 years, 3 years, 4 years, or 5 years, for example about80%-100% such as about: 80%, 90%, 95%, or 100% of the activepharmaceutical agent in the pharmaceutical composition is stable, e.g.,as measured by High Performance Liquid Chromatography (HPLC). In someembodiments, about 80%-100% (e.g., about: 90%-100% or 95-100%) ofniraparib or a pharmaceutically acceptable salt thereof (e.g., niraparibtosylate monohydrate) in the pharmaceutical composition disclosed hereinis stable for at least about: 30, 60, 90, 180, 360, 540, or 720 days,for example greater than 90 days, which can be measured by HPLC. In someembodiments, about: 80%, 85%, 90%, 95%, or 100% (e.g., about 95%) of thecrystalline Form I of niraparib tosylate monohydrate is stable for 30days or more.

In some embodiments, the pharmaceutical formulations described hereinare stable with respect to compound degradation (e.g., less than 30%,degradation, less than 25% degradation, less than 20% degradation, lessthan 15% degradation, less than 10% degradation, less than 8%degradation, less than 5% degradation, less than 3% degradation, lessthan 2% degradation, or less than 5% degradation) over a period of anyof at least about 1 day, at least about 2 days, at least about 3 days,at least about 4 days, at least about 5 days, at least about 6 days, atleast about 1 week, at least about 2 weeks, at least about 3 weeks, atleast about 4 weeks, at least about 5 weeks, at least about 6 weeks, atleast about 7 weeks, at least about 8 weeks, at least about 3 months, atleast about 4 months, at least about 5 months, at least about 6 months,at least about 7 months, at least about 8 months, at least about 9months, at least about 10 months, at least about 11 months, at leastabout 12 months, at least about 24 months, or at least about 36 monthsunder storage conditions (e.g., room temperature). In some embodiments,the formulations described herein are stable with respect to compounddegradation over a period of at least about 1 week. In some embodiments,the formulations described herein are stable with respect to compounddegradation over a period of at least about 1 month. In someembodiments, the formulations described herein are stable with respectto compound degradation over a period of at least about 3 months. Insome embodiments, the formulations described herein are stable withrespect to compound degradation over a period of at least about 6months. In some embodiments, the formulations described herein arestable with respect to compound degradation over a period of at leastabout 9 months. In some embodiments, the formulations described hereinare stable with respect to compound degradation over a period of atleast about 12 months.

Methods for assessing the chemical storage stability of solid dosageforms under accelerated aging conditions have been described in theliterature. See, e.g., S. T. Colgan, T. J. Watson, R. D. Whipple, R.Nosal, J. V. Beaman, D. De Antonis, “The Application of Science and RiskBased Concepts to Drug Substance Stability Strategies” J. Pharm. Innov.7:205-2013 (2012); Waterman K C, Carella A J, Gumkowski M J, et alImproved protocol and data analysis for accelerated shelf-lifeestimation of solid dosage forms. Pharm Res 2007; 24(4):780-90; and S.T. Colgan. R. J Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, KFields, G. Scrivens, Opportunities for Lean Stability Strategies” J.Pharm. Innov. 9:259-271 (2014).

Capsules

In some embodiments, the pharmaceutical composition is formulated intosolid oral pharmaceutical dosage forms. Solid oral pharmaceutical dosageforms include, but are not limited to, tablets, capsules, powders,granules and sachets. For example, the solid oral pharmaceutical dosageform can be a capsule.

In some embodiments, a therapeutically effective amount of niraparibadministered to a subject via a solid dosage form is in the range ofabout 1 mg to about 1000 mg. In some embodiments, the niraparib isniraparib tosylate monohydrate is a crystalline Form I substantiallyfree of Form II and Form III. Another embodiment provides thecomposition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In some embodiments, a therapeutically effective amountof niraparib administered to a subject via a solid dosage form is in therange of from about 50 mg to about 300 mg. In some embodiments, atherapeutically effective amount of niraparib administered to a subjectvia a solid dosage form is in the range of from about 50 mg to about 300mg, wherein the niraparib is niraparib tosylate monohydrate is acrystalline Form I substantially free of Form II and Form III. Anotherembodiment provides the dosage form comprising niraparib as thecrystalline Form I of niraparib tosylate monohydrate with an X-raypowder diffraction pattern substantially as shown in FIG. 1. In someembodiments, a niraparib formulation is administered as a solid dosageform at a concentration of about 50 mg to about 100 mg. In someembodiments, the niraparib formulation is administered as a solid dosageform at concentration of about 100 mg to about 300 mg. For example, atherapeutically effective amount of niraparib tosylate monohydratecrystalline Form I substantially free of Form II and Form III thereofadministered to a subject via a solid dosage form can be from about 1 mgto 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 5 mg,50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mgto 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mgto 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mgto 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mgto 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mgto 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950mg to 1000 mg. For example, a therapeutically effective amount ofniraparib tosylate monohydrate administered to a subject via a soliddosage form can be from about 1 mg to about 1000 mg, for example, fromabout 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mgto 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg,210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg,290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg,370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg,550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg,750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg,or 950 mg to 1000 mg. In some aspects, the solid oral dosage form can beadministered one, two, or three times a day (b.i.d).

For example, a therapeutically effective amount of niraparibadministered to a subject via a solid dosage form can be from about 1 mgto 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg,50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mgto 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mgto 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mgto 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mgto 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mgto 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950mg to 1000 mg. For example, a therapeutically effective amount ofniraparib tosylate monohydrate administered to a subject via a soliddosage form can be from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mgto 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mgto 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mgto 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mgto 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mgto 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments,the niraparib is niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe composition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In some aspects, the solid oral dosage form can beadministered one, two, or three times a day (b.i.d).

For example, a therapeutically effective amount of niraparibadministered to a subject via a solid dosage form can be about 1 mg to 5mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mgto 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to1000 mg. For example, a therapeutically effective amount of niraparibtosylate monohydrate administered to a subject via a solid dosage formcan be about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mgto 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mgto 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mgto 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mgto 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mgto 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mgto 950 mg, or 950 mg to 1000 mg. In some embodiments, the niraparib isniraparib tosylate monohydrate is a crystalline Form I substantiallyfree of Form II and Form III. Another embodiment provides thecomposition wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In some embodiments, a therapeutically effective amountof niraparib tosylate monohydrate administered to a subject via a soliddosage form is about 79.7 mg. In some embodiments, a therapeuticallyeffective amount of niraparib tosylate monohydrate administered to asubject via a solid dosage form is about 159.4 mg. In some embodiments,a therapeutically effective amount of niraparib tosylate monohydrateadministered to a subject via a solid dosage form is about 159.4 mg,wherein the niraparib is niraparib tosylate monohydrate is a crystallineForm I substantially free of Form II and Form III In some embodiments, atherapeutically effective amount of niraparib tosylate monohydrateadministered to a subject via a solid dosage form is about 318.8 mg. Insome embodiments, a therapeutically effective amount of niraparibtosylate monohydrate administered to a subject via a solid dosage formis about 478.2 mg. In some aspects, the solid oral dosage form can beadministered one, two, or three times a day (b.i.d).

Contemplated compositions of the present invention provide atherapeutically effective amount of niraparib over an interval of about30 minutes to about 8 hours after administration, enabling, for example,once-a-day, twice-a-day, three times a day, and etc. administration ifdesired.

In some embodiments, the weight ratio of an active pharmaceuticalingredient (e.g., niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III) to a non-activepharmaceutical ingredient (e.g., lactose monohydrate) is from about 1:10to about 10:1, respectively, for example about 1:2, about 1:3, about1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10,about 10-1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about4-1, about 3-1, or about 2:1 In some embodiments, the weight ratio of anactive pharmaceutical ingredient (e.g., niraparib tosylate monohydrateis a crystalline Form I substantially free of Form II and Form III) to anon-active pharmaceutical ingredient (e.g., magnesium stearate) is fromabout 10:1 to about 100:1, respectively, for example about 10:1, about20.1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about80:1, or about 90:1. In some embodiments, the weight ratio of anon-active pharmaceutical ingredient (e.g., lactose monohydrate ormagnesium stearate) to an active pharmaceutical ingredient (e.g.,niraparib tosylate monohydrate is a crystalline Form I substantiallyfree of Form II and Form I) to is from about 3:2 to about 11:1, fromabout 3:1 to about 7:1, from about 1:1 to about 5:1, from about 9:2 toabout 11:2, from about 4:2 to about 6:2, about 5:1, or about 2.5:1. Insome embodiments, the weight ratio of an active pharmaceuticalingredient (e.g., niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III) to a non-activepharmaceutical ingredient (e.g., lactose monohydrate or magnesiumstearate) is about 1:1.6. In some embodiments, the weight ratio of anactive pharmaceutical ingredient (e.g., niraparib tosylate monohydrateis a crystalline Form I substantially free of Form II and Form III) to anon-active pharmaceutical ingredient (e.g., lactose monohydrate ormagnesium stearate) is about 1:2. In some embodiments, the weight ratioof niraparib tosylate monohydrate to lactose monohydrate is about 38:61,for example, 38.32:61.18. In some embodiments, the weight ratio ofniraparib tosylate monohydrate to magnesium stearate is about 77:1, forexample, 76.64:1.

In some embodiments, the weight ratio of a first non-activepharmaceutical ingredient to a second non-active pharmaceuticalingredient is from about 5:1 to about 200:1, respectively, for exampleabout 5:1, about 10:1, about 20:1, about 40:1, about 50:1, about 75-1,about 100-1, about 110:1, about 120:1, about 130:1, about 140:1, about150:1, about 160:1, about 170:1, about 180:1, about 190:1, or about200:1 In some embodiments, the weight ratio of lactose monohydrate tomagnesium stearate is about 120:1 to about 125:1. In some embodiments,the weight ratio of lactose monohydrate to magnesium stearate is about122.36:1.

Indication Suitable for Treatment

Any subject having cancer, including breast cancer, ovarian cancer,cervical cancer, epithelial ovarian cancer, fallopian tube cancer,primary peritoneal cancer, endometrial cancer, prostate cancer,testicular cancer, pancreatic cancer, esophageal cancer, head and neckcancer, gastric cancer, bladder cancer, lung cancer (e.g.,adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), coloncancer, rectal cancer, thyroid cancer, brain and central nervous systemcancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoidcancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma,sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g.,hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma),myeloid disorders (e.g., AML, CML, myelodysplastic syndrome andpromyelocytic leukemia), and lymphoid disorders (e.g., leukemia,multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma,T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma) may be treated with compounds and methods described herein.

In some embodiments, the methods of the invention treat subjects withovarian cancer. In some embodiments, the methods of the invention treatsubjects with epithelial ovarian cancer. In some embodiments, themethods of the invention treat subjects with fallopian tube cancer. Insome embodiments, the methods of the invention treat subjects withprimary peritoneal cancer.

In some embodiments, the methods of the invention treat subjects withrecurrent ovarian cancer. In some embodiments, the methods of theinvention treat subjects with recurrent epithelial ovarian cancer. Insome embodiments, the methods of the invention treat subjects withrecurrent fallopian tube cancer. In some embodiments, the methods of theinvention treat subjects with recurrent primary peritoneal cancer.

In some embodiments, the methods of the invention treat subjects withrecurrent ovarian cancer following a complete or partial response to achemotherapy, such as a platinum-based chemotherapy. In someembodiments, the methods of the invention treat subjects with recurrentepithelial ovarian cancer following a complete or partial response to achemotherapy, such as a platinum-based chemotherapy. In someembodiments, the methods of the invention treat subjects with recurrentfallopian tube cancer following a complete or partial response to achemotherapy, such as a platinum-based chemotherapy. In someembodiments, the methods of the invention treat subjects with recurrentprimary peritoneal cancer following a complete or partial response to achemotherapy, such as a platinum-based chemotherapy.

In some embodiments, the methods of the invention treat subjects withrecurrent ovarian cancer, recurrent epithelial ovarian cancer, recurrentfallopian tube cancer and/or recurrent primary peritoneal cancerfollowing a complete or partial response to a platinum-basedchemotherapy, wherein the subjects begin the treatment no later than 8weeks after their most recent platinum-containing regimen. For example,subjects can begin treatment with niraparib about 7 weeks after theirmost recent platinum-containing regimen. For example, subjects can begintreatment with niraparib about 6 weeks after their most recentplatinum-containing regimen. For example, subjects can begin treatmentwith niraparib about 6 weeks after their most recent platinum-containingregimen. For example, subjects can begin treatment with niraparib about5 weeks after their most recent platinum-containing regimen. Forexample, subjects can begin treatment with niraparib about 4 weeks aftertheir most recent platinum-containing regimen. For example, subjects canbegin treatment with niraparib about 3 weeks after their most recentplatinum-containing regimen. For example, subjects can begin treatmentwith niraparib about 2 weeks after their most recent platinum-containingregimen. For example, subjects can begin treatment with niraparib about1 week after their most recent platinum-containing regimen.

In some embodiments, the methods of the invention treat subjects withprostate cancer

In some embodiments, the methods of the invention treat subjects with apediatric cancer. Exemplary pediatric cancers include, but are notlimited to adrenocortical carcinoma, astrocytoma, atypical teratoidrhabdoid tumor, brain tumors, chondroblastoma, choroid plexus tumor,craniopharyngioma, desmoid tumor, dysembryplastic neuroepithelial tumor(DNT), ependymoma, fibrosarcoma, germ cell tumor of the brain,glioblastoma multiforme, diffuse pontine glioma, low grade glioma,gliomatosis cerebri, hepatoblastoma, histiocytosis, kidney tumor, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronicmyelogenous leukemia (CML), liposarcoma, liver cancer, Burkitt lymphoma,Hodgkin lymphoma, non-Hodgkin lymphoma, malignant fibrous histiocytoma,melanoma, myelodysplastic syndrome, nephroblastoma, neuroblastoma,neurofibrosarcoma, osteosarcoma, pilocytic astrocytoma, retinoblastoma,rhabdoid tumor of the kidney, rhabdomyosarcoma, Ewing sarcoma, softtissue sarcoma, synovial sarcoma, spinal cord tumor and Wilm's tumor.

In some embodiments, the methods of the invention treat subjects with acancer with a dosage of 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg,75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg,300 mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 300 mg, 850 mg, 900 mg, 950 mg,or 1000 mg of niraparib once-daily, twice-daily, or thrice-daily. Insome embodiments, the methods of the invention treat subjects with acancer with a dosage of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg to215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 to 295mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375mg, or 370 mg to 400 mg of niraparib once-daily, twice-daily, orthrice-daily. In some embodiments, the methods of the invention treatsubjects with a cancer with a dosage of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg,50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or100 mg of niraparib once-daily, twice-daily, or thrice-daily.

In some embodiments, the methods of the invention treat subjects with acancer with a dosage of from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to20 mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg,90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg,170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg of niraparibonce-daily, twice-daily, or thrice-daily. In some embodiments, themethods of the invention treat subjects with a cancer with a dosage offrom about 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to21.5 mg, 21 mg to 23/5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to30 mg, 30 mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg,50 mg to 55 mg, 55 mg to 60 mg, 60 to 65 mg, 65 mg to 70 mg, 70 mg to 75mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or95 mg to 100 mg of niraparib once-daily, twice-daily, or thrice-daily.

Administration of the Compositions

The recommended dose of the niraparib capsule formulations describedherein as monotherapy is three 100 mg capsules taken orally once daily,equivalent to a total daily dose of 300 mg. Patients may be encouragedto take their dose at approximately the same time each day. Bedtimeadministration may be a potential method for managing nausea.

As described herein, doses of 1 to 1000 mg of niraparib may beadministered for treatment of subjects, and methods and compositionsdescribed herein may comprise once-daily, twice-daily, or thrice-dailyadministration of a dose of up to 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mgto 275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900mg, 950 mg, or 1000 mg once-daily, twice-daily, or thrice-daily. In someembodiments, the dose of niraparib is from 1 mg to 5 mg, 5 mg to 10 mg,10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg,once-daily, twice-daily, or thrice-daily. In some embodiments, themethods of the invention treat subjects with a cancer with a dosage of 1mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of niraparibonce-daily, twice-daily, or thrice-daily.

In some embodiments, a total daily dose of niraparib of 1 mg to 1000 mg,for example, or 50 to 300 mg, is administered. In some embodiments, thedaily dose of niraparib is niraparib tosylate monohydrate is acrystalline Form I substantially free of Form II and Form III Anotherembodiment provides the daily dosage wherein the crystalline Form I ofniraparib tosylate monohydrate has an X-ray powder diffraction patternsubstantially as shown in FIG. 1. In some embodiments, the total dailydose of niraparib administered exceeds 100 mg per day. In someembodiments, the total daily dose of niraparib administered exceeds 200mg per day. In some embodiments, the total daily dose of niraparibadministered exceeds 300 mg per day. In some embodiments, the totaldaily dose of niraparib administered exceeds 400 mg per day. In someembodiments, the total daily dose of niraparib administered exceeds 500mg per day.

In some embodiments, the total daily dose of niraparib administered doesnot exceed 500 mg per day. In some embodiments, the daily dose ofniraparib is niraparib tosylate monohydrate is a crystalline Form Isubstantially free of Form II and Form III. Another embodiment providesthe daily dosage wherein the crystalline Form I of niraparib tosylatemonohydrate has an X-ray powder diffraction pattern substantially asshown in FIG. 1. In some embodiments, the total daily dose of niraparibadministered does not exceed 300 mg per day. In some embodiments, thetotal daily dose of niraparib administered does not exceed 100 mg perday. In some embodiments, the total daily dose of niraparib administereddoes not exceed 50 mg per day. In some embodiments, the total daily doseof niraparib is from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg,20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900mg, 900 mg to 950 mg, or 950 mg to 1000 mg, the total daily dose ofniraparib is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg,100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or1000 mg. In some embodiments, the daily dose of niraparib is niraparibtosylate monohydrate is a crystalline Form I substantially free of FormII and Form III. Another embodiment provides the daily dosage whereinthe crystalline Form I of niraparib tosylate monohydrate has an X-raypowder diffraction pattern substantially as shown in FIG. 1.

A therapeutically effective dose of niraparib tosylate monohydrate as acrystalline Form I substantially free of Form II and Form III is about 1mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg per day. In someembodiments, the amount of niraparib administered daily is from about 1mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg,130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or950 mg to 1000 mg per day.

In some embodiments, the amount of niraparib tosylate monohydrate as acrystalline Form I substantially free of Form II and Form III isadministered one time daily is 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mgto 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mgto 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mgto 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mgto 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mgto 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments,the amount of niraparib administered one time daily is 1 mg, 5 mg, 10mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the amount of niraparib tosylate monohydrate as acrystalline Form I substantially free of Form II and Form III isadministered two times daily is 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mgto 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mgto 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mgto 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mgto 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mgto 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments,the amount of niraparib administered two times daily is 1 mg, 5 mg, 10mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the amount of niraparib tosylate monohydrate as acrystalline Form I substantially free of Form II and Form III isadministered three times daily is 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to20 mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg,90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg,170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In someembodiments, the amount of niraparib administered three times daily is 1mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the niraparib tosylate monohydrate as a crystallineForm I substantially free of Form II and Form III is present at a dosefrom about 1 mg to about 1000 mg, including, but not limited to, about 1mg, 5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0 mg,13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, 35 mg, 35.5mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49mg, 49.5 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100, 105 mg, 110 mg, 115 mg, 120 mg, 120.5 mg, 121 mg, 121.5mg, 122 mg, 122.5 mg, 123 mg, 123.5 mg, 124 mg, 124.5 mg, 125 mg, 125.5mg, 126 mg, 126.5 mg, 127 mg, 127.5 mg, 128 mg, 128.5 mg, 129 mg, 129.5mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 225 mg, 250 mg to275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, or 1000 mg.

In some embodiments, the niraparib tosylate monohydrate as a crystallineForm I substantially free of Form II and Form III is present at a dosefrom about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg,25 mg to 100 mg, 35 mg to 140 mg, 70 mg to 140 mg, 80 mg to 135 mg, 10mg to 25 mg, 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 150 mg, 150 mgto 200 mg, 10 mg to 35 mg, 35 mg to 70 mg, 70 mg to 105 mg, 105 mg to140 mg, 140 mg to 175 mg, or 175 mg to 200 mg, 35 mg to 50 mg, 50 mg to75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg,230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg,310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg,400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg,600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg,800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000mg.

Frequency of Administration

In some embodiments, a composition disclosed herein is administered toan individual in need thereof once. In some embodiments, a compositiondisclosed herein is administered to an individual in need thereof morethan once. In some embodiments, a first administration of a compositiondisclosed herein is followed by a second administration of a compositiondisclosed herein. In some embodiments, a first administration of acomposition disclosed herein is followed by a second and thirdadministration of a composition disclosed herein. In some embodiments, afirst administration of a composition disclosed herein is followed by asecond, third, and fourth administration of a composition disclosedherein. In some embodiments, a first administration of a compositiondisclosed herein is followed by a second, third, fourth, and fifthadministration ofa composition disclosed herein. In some embodiments, afirst administration of a composition disclosed herein is followed by adrug holiday.

The number of times a composition is administered to an individual inneed thereof depends on the discretion of a medical professional, thedisorder, the severity of the disorder, and the individual's response tothe formulation. In some embodiments, a composition disclosed herein isadministered once to an individual in need thereof with a mild acutecondition. In some embodiments, a composition disclosed herein isadministered more than once to an individual in need thereof with amoderate or severe acute condition. In the case wherein the patient'scondition does not improve, upon the doctor's discretion theadministration of niraparib may be administered chronically, that is,for an extended period of time, including throughout the duration of thepatient's life in order to ameliorate or otherwise control or limit thesymptoms of the patient's disease or condition.

In some embodiments, the niraparib composition is administered atpredetermined time intervals over an extended period of time. In someembodiments, the niraparib composition is administered once every day.In some embodiments, the niraparib composition is administered everyother day. In some embodiments, the niraparib composition isadministered over 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 moths,1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9years, 10 years, 11 years, or 12-15 years.

In some embodiments, the niraparib composition is administered in doseshaving a dose-to-dose niraparib concentration variation of less than50%, less than 40%, less than 30%, less than 20%, less than 10%, or lessthan 5%

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the niraparib may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days,and 365 days. A first or second dose reduction during a drug holiday maybe from 10%-100%, including by way of example only 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,and 100%. For example, a first or second dose reduction during a drugholiday may be a dose reduced from 5 mg to 1 mg, 10 mg to 5 mg, 20 mg to10 mg, 25 mg to 10 mg, 50 mg to 25 mg, 75 mg to 50 mg, 75 mg to 25 mg,100 mg to 50 mg, 150 mg to 75 mg, 100 mg to 25 mg, 200 mg to 100 mg, 200to 50 mg, 250 mg to 100 mg, 300 mg to 50 mg, 300 mg to 100 mg, 300 mg to200 mg, 400 mg to 50 mg, 400 mg to 100 mg, 400 mg to 200 mg, 500 mg to50 mg, 500 mg to 100 mg, 500 mg to 250 mg, 1000 mg to 50 mg, 1000 mg to100 mg, or 1000 mg to 500 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mgto 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mgto 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. For example, a firstor second dose reduction during a drug holiday may be a dose reduced by1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg,150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

Once improvement of the patient's condition has occurred, a maintenanceniraparib dose is administered if necessary. Subsequently, the dosage orthe frequency of administration, or both, is optionally reduced, as afunction of the symptoms, to a level at which the improved disease,disorder or condition is retained. In certain embodiments, patientsrequire intermittent treatment on a long-term basis upon any recurrenceof symptoms.

EXAMPLES

The following examples illustrate some embodiments and aspects of theinvention. It will be apparent to those skilled in the relevant art thatvarious modifications, additions, substitutions, and the like can beperformed without altering the spirit or scope of the invention, andsuch modifications and variations are encompassed with invention asdefined in the claims which follow. The invention disclosed herein isfurther illustrated by the following examples which in no way should beconstrued as being limiting.

EXPERIMENTAL TECHNIQUES X-ray Powder Diffraction (XRPD)

The Rigaku Smart-Lab X-ray diffraction system was configured forreflection Bragg-Brentano geometry using a line source X-ray beam. Thex-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and44 ma. That source provides an incident beam profile at the sample thatchanges from a narrow line at high angles to a broad rectangle at lowangles. Beam conditioning slits are used on the line X-ray source toensure that the maximum beam size is less than 10 mm both along the lineand normal to the line. The Bragg-Brentano geometry is a para-focusinggeometry controlled by passive divergence and receiving slits with thesample itself acting as the focusing component for the optics. Theinherent resolution of Bragg-Brentano geometry is governed in part bythe diffractometer radius and the width of the receiving slit used.Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1°2 θ or less. The axial divergence of the X-ray beam is controlled by5.0-degree Soller slits in both the incident and diffracted beam paths.

Powder samples were prepared in a low background Si holder using lightmanual pressure to keep the sample surfaces flat and level with thereference surface of the sample holder. Each sample was analyzed from 2to 40° 2θ using a continuous scan of 6° 2θ per minute with an effectivestep size of 0.02° 2θ. Unless otherwise noted, XPRD studies wereperformed at room temperature and room humidity.

Differential Scanning Calorimetry (DSC)

DSC analyses were carried out using a TA Instruments Q2000 instrumentThe instrument temperature calibration was performed using indium. TheDSC cell was kept under a nitrogen purge of ˜50 mL per minute duringeach analysis. The sample was placed in a standard, crimped, aluminumpan and was heated from 25° C. to 350° C. at a rate of 10° C. perminute.

Dynamic Vapor Sorption (DVS) Analysis

DVS analyses were carried out TA Instruments Q5000 Dynamic VaporSorption analyzer. The instrument was calibrated with standard weightsand a sodium bromide standard for humidity. Samples were analyzed at 25°C. with a maximum equilibration time of 60 minutes in 10% relativehumidity (RH) steps from 5 to 95% RH (adsorption cycle) and from 95 to5% RH (desorption cycle).

Example 1: Water Activity Studies

Slurry experiments designed to provide a range of water activities werecarried out in solvent mixtures containing water and dimethylsulfoxide(Table 1). The anhydrate appears to be the preferred form at wateractivities of 0.11 or less and the monohydrate appears to be thepreferred form at water activities of 0.22 or more. The amorphous haloobserved in many of the patterns is due to solvent. The samples wereanalyzed while wet to avoid changes, such as the hydrate converting tothe anhydrate, from drying.

TABLE 1 Solvent Water Time XRPD (% water in DMSO) activity (days) Result0 0 2 anhydrate 9.8 0.11 2 anhydrate 17.2 0.22 2 hydrate 27.6 0.38 2hydrate 43.3 0.60 2 hydrate 82.8 0.84 2 hydrate 100.0 1.00 2 hydrate

Example 2: Preparation of Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

A batch of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidetosylate which is a mixture of Form I, Form II and Form II is dissolvedin water:DMSO/200.1 to reach a concentration of about 0.15 M. Theresulting mixture is heated until dissolution occurs and is then cooledto about 25° C. overnight. The resulting solid is collected, dried andanalyzed by x-ray powder diffraction, differential scanning calorimetry,Raman spectroscopy, infrared spectroscopy, dynamic water vapor sorption,or any combination thereof, to determine the presence of Form II or FormIII. FIG. 6 provides an overlay comparison of the x-ray powderdiffraction patterns for Form I and Form III. FIG. 9 provides an overlaycomparison of the x-ray powder diffraction patterns for Form I, Form IIand Form III.

Example 3: Preparation of Anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

Niraparib 4-toluenesulfonate monohydrate (3.01 g) was suspended in 110mL of toluene, and the resulting mixture was heated to reflux for 2hours, collecting toluene/water into a Dean-Stark trap. A small amountof water was observed in the trap. The slurry was allowed to cool toambient temperature, vacuum filtered, and the solids air dried.

Example 4: Characterization of Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide X-Ray PowderDiffraction

FIGS. 1 and 6 provide the X-ray powder diffraction pattern forcrystalline Form I monohydrate of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Table 2provides a listing of the reflections.

TABLE 2 Pos. [°2Th.] d-spacing [Å] Height [cts| FWHM [°2Th.] 6.587913.40619 460.5 0.5288 6.985 12.64485 477.57 0.823 9.0602 9.75275 2868.980.4263 9.524 9.27879 78535.62 0.1109 11.7927 7.49835 1707.43 0.1.24312.355 7.15828 54936.48 0.1168 12.6092 7.01457 1188.76 0.0993 13.22136.69113 35563.92 0.1254 13.5062 6.55063 569.25 0.3698 13.8394 6.393686772.92 0.1125 13.9958 6.32258 6011.08 0.1324 14.1943 6.23457 16335.010.1248 14.6912 6.0248 24730.51 0.1255 14.858 5.95753 27991.59 0.116915.0707 5.87396 18385.48 0.1353 15.3794 5.75672 2780.53 0.1073 15.58815.68013 3779.759 0.1025 16.3332 5.42265 9823.46 0.1415 16.617 5.330672329.47 0.201 17.4264 5.08485 50122.63 0.1333 17.573 5.042.76 8100.610.3643 17.8849 4.95552 2229.24 0.1546 18.427 4.81093 204163.1 0.172118.8482 4.70436 3012.17 0.1544 19.177 4.62444 14586.06 0.166 19.47064.55535 8731.12 0.1299 19.9266 4.45213 21822.89 0.1538 20.2412 4.383646045.22 0.1614 21.0044 4.22605 63640.16 0.1445 21.5548 4.11937 10560.250.1515 22.2131 3.99876 753.36 0.1605 22.9905 3.8652.6 4058.7 0.164623.1768 3.83462 7387.16 0.1302 23.6115 3.76499 6636.48 0.3093 23.80733.73447 3271.55 0.0929 24.2164 3.6723 21759.7 0.1697 24.4265 3.641196345.06 0.161 24.9128 3.5712 103096 0.1575 25.5764 3.48002 47498.830.1529 26.0348 3.41979 99687.98 0.1845 26.9234 3.3089 32700.42 0.186627.4696 3.24434 21472.77 0.1595 27.9243 3.19253 1792.33 0.1146 28.32953.14778 1967.85 0.8105 28.6335 3.11505 13930.93 0.1549 29.1807 3.0578712702.19 0.1798 29.6703 3.00852 6677.41 0.4434 29.9963 2.97655 16868.650.1759 30.3008 2.94733 6812.67 0.1494 30.508 2.92779 14421.1 0.195631.0316 2.87957 5755.4 0.1828 31.5213 2.83594 5497.13 0.179 32.5752.74657 498.46 0.1586 32.9187 2.71867 3851.61 0.2345 33.532 2.670342240.41 0.2865 33.8569 2.64546 1516.95 0.2802 34.4808 2.599 1196.670.1616 35.0202 2.5602 3988.39 0.2523 35.4178 2.53236 2443.9 0.137435.5372 2.52412 2795 0.2115 36.1608 2.48202 5523.84 0.2396 37.39962.4026 5344.49 0.2021 37.7359 2.38196 1623.87 0.2622 38.2141 2.353244115.75 0.203 38.55 2.33351 1414.01 0.1982 38.8559 2.31584 6323.460.1835 30.508 2.92779 14421.1 0.1956 31.0316 2.87957 5755.4 0.1828

Differential Scanning Calorimetry (DSC)

FIG. 2 shows an exemplary scanning differential calorimetry pattern forcrystalline monohydrate Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DSCcurve of the monohydrate exhibits an endotherm at approximately 154° C.which is likely due to dehydration followed by an endotherm atapproximately 231° C. which is likely due to melting.

Dynamic Vapor Sorption (DVS) Analysis

FIG. 5 shows an exemplary dynamic water vapor sorption pattern forcrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DVScurve of the monohydrate indicates the monohydrate is not hygroscopic.After the experiment the samples were analyzed by XRPD. The monohydrateremained unchanged.

Example 5: Characterization of anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide X-Ray PowderDiffraction

FIGS. 6 and 7 provide the X-ray powder diffraction pattern forcrystalline anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Table 3provides a listing of the reflections.

TABLE 3 Pos. [°2Th.] d-spacing [Å] Height [cts] FWHM [°2Th.] 7.849911.25339 895.67 0.1707 9.5009 9.3012.6 2320.94 0.1654 10.2259 8.643444750.18 0.2032 10.9698 8.05886 18992.07 0.164 11.2525 7.85708 10175.980.1595 11.7171 7.54655 3014.31 0.1668 12.1661 7.26901 1145.84 0.227312.9299 6.84128 6553.68 0.1857 13.5713 6.51937 14717.58 0.1828 14.13766.25944 13082.42 0.2387 15.78 5.61146 13659.23 0.236 16.6445 5.321910574.32 0.39 16.8657 5.25261 9058.46 0.3716 17.4485 5.07847 51335.750.2087 17.814 4.97508 86267.17 0.1798 18.0524 4.90991 19854.59 0.272918.9679 4.67494 123782.4 0.199 19.1913 4.62102 31339.04 0.4525 19.94664.44771 3909.81 0.1923 20.5575 4.3169 10356.35 0.2796 21.2948 4.169073968.5 0.4668 22.0804 4.02248 4071.42 0.1664 22.7882 3.89912 32060.480.3358 23.7401 3.74489 21269.23 0.2247 24.8296 3.58298 11374.86 0.381825.2491 3.5244 9542.6 0.2188 25.471 3.49419 12822.77 0.2109 25.97893.42702 898.11 0.3533 26.5278 3.35734 1135.46 0.3302 26.9336 3.307678691.48 0.176 27.3191 3.26186 4697.95 0.304 27.5324 3.23707 7412.050.279 28.3515 3.14539 5097.68 0.1787 29.1345 3.06262 4974.1 0.25429.6226 3.01325 685.05 0.0579 30.06 2.97039 3581.07 0.1928 30.69132.91071 1865.07 0.223 31.7871 2.81283 8828.05 0.5478 32.9385 2.71709884.34 0.3145 33.3656 2.68328 1576.57 0.2445 34.2199 2.61822 1560.90.3393 34.9489 2.56526 699.93 0.2234 36.0738 2.4878 1800.14 0.249136.7177 2.44564 2321.23 0.3452 37.1849 2.41597 800.76 0.3354 38.48312.33741 2823.91 0.3912 38.7512 2.32185 925.86 0.3342 39.0789 2.30313877.67 0.3596 39.8123 2.26238 765.08 0.5313

Differential Scanning Calorimetry (DSC)

FIG. 2 shows an exemplary scanning differential calorimetry pattern forcrystalline anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DSCcurve of the anhydrate exhibits an endotherm at approximately 230° C.which is likely due to melting.

Dynamic Vapor Sorption (DVS) Analysis

FIG. 8 shows an exemplary dynamic water vapor sorption pattern forcrystalline anhydrous Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DVScurve of the anhydrate is very hygroscopic and showed a weight gain ofapproximately 15.8% up to 95% RH. After the experiment the samples wereanalyzed by XRPD. The anhydrate converted to the monohydrate.

Paragraphs of the Embodiments

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

The composition of paragraph [00133], wherein the crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-raypowder diffraction pattern substantially as shown in FIG. 1.

The composition of paragraph [00133] or [00134], wherein the crystallineForm I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by at least one X-ray diffraction pattern reflectionselected from a 2θ value of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2,18.4±0.2, 21.0±0.2, 24 9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0 2.

The composition of any one of paragraphs [00133]-[00135], wherein thecrystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide ischaracterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2.

The composition of paragraph [00136], wherein the crystalline Form I isfurther characterized by X-ray diffraction pattern reflections at 2θvalue of 9.5±0.2 and 26.0±0.2.

The composition of paragraph [00136] or [00137], wherein the crystallineForm I is further characterized by X-ray diffraction pattern reflectionsat a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2,25.6±0.2, and 26.9±0.2.

The composition of paragraph [00136] or [00137], wherein the crystallineForm I is further characterized by at least one X-ray diffractionpattern reflection selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.

The composition of paragraph [00136] or [00137], wherein the crystallineForm I is further characterized by at least two X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.

The composition of paragraph [00136] or [00137], wherein the crystallineForm I is further characterized by at least three X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2,17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.

The composition of paragraph [00136] or [00137], wherein the crystallineForm I is further characterized by at least four X-ray diffractionpattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 174±0.2, 18.4±0.2, 21.0±0.2, 25.6±0 2, and 26.9±0.2.

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein thecrystalline Form I is characterized by a scanning differentialcalorimetry pattern substantially as shown in FIG. 2.

The composition of paragraph [00143], wherein the composition is thecomposition of any one of paragraphs [00133]-[00142].

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein thecrystalline Form I is characterized by a Raman spectroscopy patternsubstantially as shown in FIG. 3.

The composition of paragraph [00145], wherein the composition is thecomposition of any one of paragraphs [00133]-[00144].

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein thecrystalline Form I is characterized by a dynamic water vapor sorptionpattern substantially as shown in FIG. 5.

The composition of paragraph [00147], wherein the composition is thecomposition of any one of paragraphs [00133]-[00146].

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein thecrystalline Form I is characterized by an infrared spectroscopy patternsubstantially as shown in FIG. 4.

The composition of paragraph [00149], wherein the composition is thecomposition of any one of paragraphs [00133]-[00148].

The composition of any one of paragraphs [00133]-[00150], wherein thepresence of Form III is characterized by at least one X-ray diffractionpattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or22.8±0.2.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form III means less than about 20%(w/w) combined total weight for Form II and Form III compared to thecombined total weight of Form I. Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form III means less than about 15%(w/w) combined total weight for Form II and Form III compared to thecombined total weight of Form I, Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form III means less than about 10%(w/w) combined total weight for Form II and Form III compared to thecombined total weight of Form I, Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form II means less than about 8% (w/w)combined total weight for Form II and Form III compared to the combinedtotal weight of Form I, Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form III means less than about 6%(w/w) combined total weight for Form II and Form III compared to thecombined total weight of Form I. Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form III means less than about 4%(w/w) combined total weight for Form II and Form III compared to thecombined total weight of Form I, Form II and Form II.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form I and Form III means less than about 3% (w/w)combined total weight for Form II and Form III compared to the combinedtotal weight of Form I. Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form II means less than about 2% (w/w)combined total weight for Form II and Form III compared to the combinedtotal weight of Form I, Form II and Form III.

The composition of any one of paragraphs [00133]-[00151], whereinsubstantially free of Form II and Form II means less than about 1% (w/w)combined total weight for Form II and Form III compared to the combinedtotal weight of Form I, Form II and Form III.

A composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

A composition comprising crystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

A composition comprising crystalline Form II2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

The composition of any one of paragraphs [00161]-[00163], wherein thecrystalline Form II is characterized by at least one X-ray diffractionpattern reflection selected from a 2θ value of 9.7±0.3, 12.8±0.3,17.9±0.3, 19.7±0.3, and 21.8±0.3.

The composition of any one of paragraphs [00161]-[00164], wherein thecrystalline Form II has an X-ray powder diffraction patternsubstantially as shown in FIG. 9 for Form II.

A composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide andcrystalline Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

A composition comprising crystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.

The composition of any one of paragraphs [00163]-[00167], wherein thecrystalline Form III is characterized by at least one X-ray diffractionpattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or22.8±0.2.

The composition of any one of paragraphs [00163]-[00167] wherein thecrystalline Form III has an X-ray powder diffraction patternsubstantially as shown in FIG. 9 for Form III.

The composition of any one of paragraphs [00163]-[00167], wherein thecrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-raypowder diffraction pattern substantially as shown in FIG. 7.

The composition of any one of paragraphs [00163]-[00170], wherein thecrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a dynamic water vapor sorption pattern substantially asshown in FIG. 8.

The composition of any one of paragraphs [00163]-[00171], wherein thecrystalline Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidecharacterized by a scanning differential calorimetry patternsubstantially as shown in FIG. 2.

A method of making crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, comprisingdissolving a composition comprising Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form IIIof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or amixture thereof, in a solvent having a water:organic solvent ratio ofabout 10:1 to about 400:1 (v/v), and crystallizing the crystalline FormI.

The method of paragraph [00173], wherein the water:organic solvent ratiois about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1(v/v), about 300:1 (v/v), or about 400:1 (v/v).

The method of paragraph [00173], wherein the organic solvent is a polarsolvent, a polar protic solvent, a polar aprotic solvent, anether-containing solvent, or any combination thereof.

The method of paragraph [00173], wherein the organic solvent is2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid,formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, orany combination thereof.

The method of paragraph [00173], wherein the organic solvent is acetone,methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane,dimethyl sulfoxide, or any combination thereof.

The method of paragraph [00173], wherein the organic solvent is2-propanol, acetic acid, formic acid, or any combination thereof.

The method of paragraph [00173], wherein the organic solvent and wateris heated prior to crystallization.

A composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide as describedin any one of paragraphs 1-[00160], prepared by dissolving a compositioncomprising Form II of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form IIIof 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or amixture thereof, in a solvent having a water:organic solvent ratio ofabout 10:1 to about 400:1 (v/v), and crystallizing the crystalline FormI.

The composition of paragraph [00180], wherein the water:organic solventratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).

The composition of paragraph [00180], wherein the organic solvent is apolar solvent, a polar protic solvent, a polar aprotic solvent, anether-containing solvent, or any combination thereof.

The composition of paragraph [00180], wherein the organic solvent is2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid,formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, orany combination thereof.

The composition of paragraph [00180], wherein the organic solvent isacetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether,dioxane, dimethyl sulfoxide, or any combination thereof.

The composition of paragraph [00180], wherein the organic solvent is2-propanol, acetic acid, formic acid, or any combination thereof.

The composition of paragraph [00180], wherein the organic solvent andwater is heated prior to crystallization.

The composition of any one of paragraphs [00133]-[00172] and[00180]-[00186], wherein the composition is a pharmaceuticalcomposition.

A pharmaceutical composition comprising crystalline Form I of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamidesubstantially free of Form II and Form III of2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and atleast one pharmaceutically acceptable excipient.

The pharmaceutical composition of any one of paragraphs [00133]-[00188],wherein the composition is in an oral dosage form.

The pharmaceutical composition of paragraph [00189], wherein the oraldosage form is a tablet or capsule

An article of manufacture comprising multiple unit doses of thepharmaceutical composition of any of paragraphs [00187]-[00190] in asealed container with written instructions for use.

The article of manufacture of paragraph [00191], further comprising aninduction seal, desiccant, or any combination thereof.

The pharmaceutical composition of paragraph [00187] or [00188] whereinthe composition is in unit dose form.

1. A crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate substantially free of Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 9.5±0.2, 24.9±0.2, and 26.0±0.2 degrees; and wherein substantially free of Form II and Form III means the composition comprises less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form L Form II, and Form III; and wherein Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3 degrees; and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate is substantially characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 17.8±0.2, 19.0±0.2, and 22.8±0.2 degrees.
 2. The crystalline Form I of claim 1, wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by has an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.
 1. 3.-5. (canceled)
 6. The crystalline Form I of claim 1, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees. 7.-8. (canceled)
 9. The crystalline Form I of claim 1, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
 10. The crystalline Form I of claim 1, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
 11. The crystalline Form I of claim 1, wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG.
 2. 12. (canceled)
 13. The crystalline Form I of claim 1, wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown in FIG.
 3. 14. (canceled)
 15. The crystalline Form I of claim 1, wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG.
 5. 16. (canceled)
 17. The crystalline Form I of claim 1, wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG.
 4. 18.-40. (canceled)
 41. The crystalline Form I of claim 1, wherein the crystalline Form I is prepared by a method comprising dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I. 42.-61. (canceled)
 62. A method of treating a patient diagnosed with ovarian cancer, fallopian tube cancer, epithelial ovarian cancer, recurrent ovarian cancer, prostate cancer, colon cancer, or rectal cancer comprising: administering to the patient a pharmaceutically acceptable dose of a crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate substantially free of Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate; wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 9.5±0.2, 24.9±0.2, and 26.0±0.2 degrees; and wherein substantially free of Form II and Form III means the composition comprises less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II, and Form III; and wherein Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3 degrees; and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate is substantially characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 17.8±0.2, 19.0±0.2, and 22.8±0.2 degrees.
 63. The method of claim 62, wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.
 1. 64. The method of claim 62, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles at 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
 65. The method of claim 62, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
 66. The method of claim 62, wherein the crystalline Form I is further characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
 67. The method of claim 62, wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG.
 2. 68. The method of claim 62, wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown in FIG.
 3. 69. The method of claim 62, wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG.
 5. 70. The method of claim 62, wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG.
 4. 71. The method of claim 62, wherein the crystalline Form I is prepared by a method comprising dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate, non-stoichiometric hydrate or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I. 